Harold I Feldman, M.D., M.S.C.E. is a Professor of Medicine and Epidemiology applying to renew a Mid-career Award in Patient Oriented Research (K24). Dr. Feldman has completed his first term of his K24 with an outstanding record of both mentorship and accomplishment in his patient-oriented research program focusing on kidney disease broadly and renal transplantation more specifically. For this renewal application, Dr. Feldman will continue his mentoring activities for both post-doctoral trainees and junior clinician researchers. He anticipates being the primary faculty mentor for 2 to 3 mentees per year in addition to providing mentorship for faculty in his research Division of Epidemiology. His patient oriented research activities will continue to address problems in chronic kidney disease, but will now focus on the period of disease before individuals become dependent on dialysis or transplantation. Dr. Feldman, will extend his work with and leadership of the NIDDK's Chronic Renal Insufficiency Cohort (CRIC) Study, a 3000-person national cohort study of the intersection of chronic kidney disease (CKD) and cardiovascular illness (CVD). CRIC is nearing completion of recruitment and provides an ideal platform on which to conduct the study of insulin resistance Dr. Feldman proposes. Building on CRIC, the proposed study will be one of the first investigations into insulin resistance and the metabolic syndrome in chronic kidney disease which afflicts over 20 million Americans. The enormous burden of cardiovascular disease among individuals with renal insufficiency makes urgent investigations that will explore mechanisms of accelerated vascular disease in this setting and identify. Insulin resistance is a potent risk factor for cardiovascular disease among individuals without chronic kidney disease and commonly co-exists with renal insufficiency. The principal goals of the proposed study are to determine the relationships of insulin resistance to the level of renal function, to other features of the metabolic syndrome, to CVD events, and to progression of kidney disease. Exploration of insulin metabolism in CKD will be a secondary aim. This study will use a validated measure of insulin resistance calculated from fasting insulin and glucose levels for all CRIC subjects. Both cross- sectional and longitudinal analyses will expand our understanding of the excess risk of CVD and identify potential targets for novel therapies to reduce CVD burden in the setting of CKD.